Tumor necrosis factor α in aGVHD patients contributed to the impairment of recipient bone marrow MSC stemness and deficiency of their hematopoiesis-promotion capacity

Abstract

Background: Though accumulated evidence has demonstrated visceral organ involvement in acute graft-versushost disease (aGVHD), how aGVHD influences the bone marrow (BM) niche and the reconstitution of hematopoiesis post-hematopoietic stem cell transplantation remains largely unknown. Methods: In the current study, the cell morphology, immunophenotype, multi-differentiation capacity, self-renewal capacity, and hematopoiesis promotion of the MSCs from aGVHD and non-aGVHD patients were investigated. Additionally, the stemness and hematopoiesis-promoting property of healthy donor-derived MSCs were evaluated in the presence of BM supernatant from aGVHD patients. Mechanistically, antibodies targeting inflammatory cytokines involved in aGVHD were added into the MSC culture. Furthermore, a recombinant human tumor necrosis factor (TNF-α) receptor-Ig fusion protein (rhTNFR:Fc) was used to protect healthy donor-derived MSCs. Moreover, mRNA sequencing was performed to explore the underlying mechanisms. Results: The aGVHD MSCs exhibited morphological and immunophenotypic characteristics that were similar to those of the non-aGVHD MSCs. However, the osteogenic and adipogenic activities of the aGVHD MSCs significantly decreased. Additionally, the colony formation capacity and the expression of self-renewal-related genes remarkably decreased in aGVHD MSCs. Further, the hematopoiesis-supporting capacity of aGVHD MSCs significantly reduced. The antibody neutralization results showed that TNF-α contributed to the impairment of MSC properties. Moreover, rhTNFR:Fc exhibited notable protective effects on MSCs in the aGVHD BM supernatants. The mRNA sequencing results indicated that the TNF-α pathway and the Toll-like receptor pathway may be activated by TNF-α.

Clinical-grade hDPSCs Suppressed the Activation of Osteoarthritic Macrophages and Attenuated Cartilaginous Damage in a Rabbit OA Model

“…Li et al found that the stromal niche of gastric cancer contributed to macrophage polarization within the gastric cancer niche through considerable secretion of IL-6 and IL-8 [48]. Additionally, our previous studies demonstrated that MSCs were capable of controlling the differentiation fate of monocytes, which are important progenitors of macrophages [21,25]. Thus, we explored the possibility of osteoarthritic macrophage control by hDPSCs.…”

“…Synovial uid from OA patients (OASF) is a potent in ammatory mediator that includes numerous in ammatory cytokines and has been reported to promote osteochondral lesions in osteoarthritis [21,34,35]. In the current study, OASF was used to mimic the joint microenvironments of OA and to cultivate osteoarthritic macrophages.…”

“…In the current study, OASF was used to mimic the joint microenvironments of OA and to cultivate osteoarthritic macrophages. Human OASF was harvested from the knee joints of 10 patients with OA with previous protocols [21] (Tab. S1).…”

“…In recent decades, we have been pursuing preclinical research and clinical applications of stem cell-based therapy for the treatment of severe diseases [19][20][21][22][23][24][25][26][27][28][29]. Notably, we explored the therapeutic effects of hDPSCs on several skeletal disorders, including rheumatoid arthritis, osteoporosis, and tooth loss [30][31][32].…”

Wnt/β-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients

“…For example, the number of MSCs and the osteogenic capacity increased in the RA mouse model 20 , and MSCs from the patients with SLE had a morphological appearance of senescence and impaired capabilities of differentiation 19 . In regard to the relationship between MSCs and the pathogenesis of GVHD, a few studies reported that the number of MSCs were decreased and differentiation was abnormal in aGVHD patients 22 , 23 . But it is rarely reported whether MSCs were abnormal in cGVHD patients.…”